T细胞受体
脱磷
生物
泛素连接酶
细胞生物学
泛素
T细胞
自分泌信号
磷酸化
磷酸酶
Jurkat细胞
信号转导
受体
生物化学
免疫系统
免疫学
基因
作者
Yuan-Li Tsai,Marcel Arias-Badia,Theresa A. Kadlecek,Yee May Lwin,Aahir Srinath,Neel H. Shah,Zhi-En Wang,Diane L. Barber,John Kuriyan,Lawrence Fong,Arthur Weiss
出处
期刊:Immunity
[Elsevier]
日期:2023-12-01
卷期号:56 (12): 2682-2698.e9
被引量:1
标识
DOI:10.1016/j.immuni.2023.11.010
摘要
Summary
T cell responses are inhibited by acidic environments. T cell receptor (TCR)-induced protein phosphorylation is negatively regulated by dephosphorylation and/or ubiquitination, but the mechanisms underlying sensitivity to acidic environments are not fully understood. Here, we found that TCR stimulation induced a molecular complex of Cbl-b, an E3-ubiquitin ligase, with STS1, a pH-sensitive unconventional phosphatase. The induced interaction depended upon a proline motif in Cbl-b interacting with the STS1 SH3 domain. STS1 dephosphorylated Cbl-b interacting phosphoproteins. The deficiency of STS1 or Cbl-b diminished the sensitivity of T cell responses to the inhibitory effects of acid in an autocrine or paracrine manner in vitro or in vivo. Moreover, the deficiency of STS1 or Cbl-b promoted T cell proliferative and differentiation activities in vivo and inhibited tumor growth, prolonged survival, and improved T cell fitness in tumor models. Thus, a TCR-induced STS1-Cbl-b complex senses intra- or extra-cellular acidity and regulates T cell responses, presenting a potential therapeutic target for improving anti-tumor immunity.
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